Abstract
Estrogen (E2) receptor (ER) upregulation has been associated with tumor progression and is the most commonly used clinical biomarker in breast cancer. X‑linked ribosomal S6 kinase 4 (RSK4) is downregulated in breast cancer and may act as a tumor suppressor gene. In order to understand the association between the ER and RSK4, the present study studied the effects of RSK4 on ER‑positive (ER+) breast cancer cell function, and the effects of E2 on RSK4 function and RSK4 methylation. Furthermore, the disease‑free survival of patients with breast cancer with RSK4 hypermethylation/hypomethylation was investigated to establish the link between RSK4 methylation on patient prognosis. The expression levels of RSK4 were increased and RSK4 promoter methylation was decreased in ER+ breast cancer tissues and cell lines compared with ER‑negative breast cancer tissues and cell lines, respectively. ER expression was negatively correlated with RSK4 expression and positively associated with RSK4 methylation. In vitro overexpression of RSK4 decreased the proliferation, clone formation, migration and angiogenesis and increased apoptosis of breast cancer cells. Patients with RSK4 hypomethylation exhibited a longer disease‑free survival compared with patients with RSK4 hypermethylation. E2 stimulation of breast cancer cells increased ER expression and RSK4 methylation, which was associated with decreased RSK4 expression. Furthermore, ER upregulation was proposed to be related to the decreased expression of RSK4 in ER+ breast cancer. E2 signaling may therefore act upstream of RSK4 to promote cancer progression. The results obtained in the current study suggested that RSK4 inhibited breast cancer cell invasiveness and that RSK4 promoter hypomethylation may serve as a novel prognostic marker for patients with breast cancer.